UNIVERSITI PUTRA MALAYSIA

ANTI-AGEING PROPERTIES OF EDIBLE BIRD'S NEST ASCERTAINED BY IN VITRO AND IN VIVO STUDIES IN ANIMAL MODEL

HOU ZHIPING

IB 2015 18

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ANTI-AGEING PROPERTIES OF EDIBLE BIRD'S NEST ASCERTAINED BY

IN VITRO AND IN VIVO STUDIES IN ANIMAL MODEL

By

HOU ZHIPING

Thesis Submitted to the School of Graduate Studies, Universiti Putra Malaysia, in

Fulfillment of the Requirements for the degree of Doctor of Philosophy

August 2015

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COPYRIGHT

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icons, photographs and all other artwork, is copyright material of Universiti Putra

Malaysia unless otherwise stated. Use may be made of any material contained within

the thesis for non-commercial purposes from the copyright holder. Commercial use of

material may only be made with the express, prior, written permission of Universiti

Putra Malaysia.

Copyright © Universiti Putra Malaysia

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Specially dedicated to,

My parents, husband and daughter

For their invaluable love, dedication, encouragement and patience

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Abstractof thesis presented to the Senate of Universiti Putra Malaysia in fulfillment of

the requirement for the Doctor of Philosophy

ANTI-AGEING PROPERTIES OF EDIBLE BIRD'S NEST ASCERTAINED BY

IN VITRO AND IN VIVO STUDIES IN ANIMAL MODEL

By

HOU ZHIPING

August 2015

Chairman: Maznah binti Ismail, PhD

Faculty : Institute of Bioscience

According to the World Health Organization (WHO), the world average life

expectancy as at 2014 is 66.26 years, having an average of 64.30 years for males and

68.35 years for females. However, the onset of menopause for women, usually around

50 years, has not been postponed along with increasing longevity, but rather brought

forward due to the impacts of environment, diet, and lifestyle. Most women spend

approximately one-third of their life span in the postmenopausal phase. Hormonal

imbalance during menopausal stage has been linked to increased risks of the fatal

diseases including Alzheimer’s disease, dementia, stroke, diabetes mellitus, and breast

cancer. Hormone replacement therapy (HRT) has been used to restore postmenopausal

hormonal levels in order to relieve menopausal problems, but its associated side effects

including development of cancers and cardiovascular diseases have necessitated the

search for other alternatives such as natural food supplementation.

Edible bird’s nest (EBN) from the saliva of swiftlet has been esteemed as a precious

food tonic by Chinese people since the Tang dynasty (618AD) because it contains rich

amount of bioactive compounds such as water - soluble proteins, carbohydrate, iron,

inorganic salt, and fiber, and is reported to traditionally possess anti-ageing, anti -

cancer, and immunity - enhancing properties. Evidence-based details of its anti-ageing

effects including underlying mechanisms are lacking. In this study, EBN was evaluated

for its anti - ageing effects and its potential mechanisms were evaluated. First of all,

ovariectomized female Sprague - Dawley rats were fed with EBN (6 %, 3 % and 1.5 %

in normal pellet) for 12 weeks, then, cognitive function, metabolic indices (serum

estrogen, insulin, liver enzyme, kidney function, lipid profile, and antioxidant markers)

and hippocampal sirtuin - 1 protein level were in comparison with non - treated

ovariectomized rats were observed, and in some instances it showed better results than

estrogen therapy. Additionally, EBN produced better transcriptional regulation of

hippocampal anti-oxidant genes and an Alzheimer disease isrelated genes, and hepatic

insulin signaling genes. Moreover, EBN and its constituents (lactoferrin and

ovotransferrin) attenuated H2O2 - induced cytotoxicity, and decreased radical oxygen

species through increased scavenging activity, with corresponding transcriptional

changes in anti - oxidant and apoptosis - related genes that tended towards

neuroprotection.

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These data suggested that EBN reduced the risks of neurodegenerative diseases, and

may be used as functional ingredient for the prevention of neurodegenerative and

metabolism related diseases associated with estrogen deficient ageing.

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Abstrak tesis yang dikemukakan kepada Senat Universiti Putra Malaysia sebagai

memenuhi keperluan untuk ijazah Doktor Falsafah

SIFAT ANTI-PENUAAN SARANG BURUNG WALIT DITENTUKAN

MELALUI KAJIAN IN VITRO DAN MODEL HAIWAN IN VIVO

Oleh

HOU ZHIPING

Ogos 2015

Pengerusi: Maznah binti Ismail, PhD

Fakulti : Institut Biosains

Menurut Pertubuhan Kesihatan Sedunia (WHO), purata jangka hayat manusia di dunia

pada 2014 adalah 66.26 tahun, di mana lelaki mempunyai purata 64.3 tahun manakala

wanita mempunyai 68.35 tahun. Walau bagaimanapun, permulaan menopaus bagi

wanita, biasanya sekitar 50 tahun, tidak ditangguhkan bersama - sama dengan

peningkatan umur, tetapi sebaliknya dipercepatkan oleh kesan persekitaran, diet dan

gaya hidup. Kebanyakan wanita menghabiskan kira-kira satu pertiga daripada jangka

hayat mereka dalam fasa menopaus. Ketidakseimbangan hormon semasa menopaus

telah dikaitkan dengan peningkatan risiko penyakit - penyakit kronik termasuk

penyakit Alzheimer, nyanyuk, strok, kencing manis, dan kanser payudara. Terapi

penggantian hormon (HRT) telah digunakan untuk mengubati masalah putus haid,

tetapi kesan sampingan seperti kanser dan penyakit kardiovaskular telah mendorong

pencarian alternatif lain seperti suplemen makanan semulajadi.

Sarang burung (EBN) daripada air liur burung walit telah digelarkan sebagai tonik

makanan yang berharga oleh orang-orang Cina sejak Dinasti Tang (618AD) kerana ia

mengandungi jumlah sebatian bioaktif yang kaya seperti protein larut air, karbohidrat,

besi, garam bukan organik, dan serat. Ia juga dilaporkan secara tradisi mempunyai anti

- penuaan, anti - kanser, dan sifat - sifat meningkatkan imuniti. Maklumat berasaskan

bukti saintifik kesan anti - penuaan termasuk mekanisme kefungsiannya adalah amat

sedikit. Dalam kajian ini, kesan anti - penuaan daripada EBN telah dikaji dan

mekanisme yang berpotensi juga ditentukan. Pertamanya, tikus Sprague-Dawley betina

“yang dibuang ovari” yang diberi makan EBN (1.5 %, 3 %, dan 6% dalam normal

pelet) selama 12 minggu menunjukkan fungsi kognitif, indeks metabolik (serum

estrogen, insulin, hati fungsi buah pinggang enzymesm, profil lipid, dan penanda

antioksidan) dan protein sirtuin – 1 pada hippocampus adalah lebih baik berbanding

dengan tikus yang dibuang ovari tanpa makanan EBN, dan dalam keadaan tertentu ia

menunjukkan keputusan yang lebih baik berbanding dengan terapi estrogen. Di

samping itu, EBN menunjukkan pengawalan transkripsi gen yang lebih baik termasuk

gen anti-oksida dan gen berkaitan dengan penyakit Alzheimer pada tisu hippocampus,

dan juga gen isyarat insulin hepatik. Tambahan pula, EBN dan sebatian aktif

(laktoferin, LF dan ovotransferrin, OVF) melemahkan sitotoksiti yang disebabkan oleh

H2O2, dan menurunkan spesies oksigen radikal (ROS) melalui peningkatan aktiviti

memerangkap radikal, dengan mengubah transkripsi gen yang berkaitan dengan anti -

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oksida dan apoptosis, justeru menunjukkan kecenderungan ke arah perlindungan sistem

neuron.

Data mencadangkan bahawa EBN mengurangkan risiko penyakit sistem neuron dan

boleh digunakan sebagai bahan nutrasutikal untuk mencegah penyakit neuron dan

penyakit metabolik yang dikaitkan dengan kekurangan estrogen.

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ACKNOWLEDGEMENTS

I would like to extend my deepest gratitude and appreciation to my supervisor Prof. Dr.

Maznah Ismail for her endless support, generous guidance and constructive advice that

contributed to the completion of this project.

My sincere gratitude also goes to my co - supervisors Prof. Dr. Rozi Mahmud and Prof.

Dr. Aini Ideris, thank you for the her priceless comments and invaluable advice.

I would also like to acknowledge and thank Dr. Mustapha Umar Imam for his careful

reviews and constructive criticism throughout the entire course of this research. Not

forgetting all the staffs in the Laboratory of Molecularmedicine, my sincere thanks to

them, especially Mrs. Norsharina Ismail, Mr. Chan Kimwei, and Mrs Norhayat Yusuf

for their assistance in laboratory management. I am grateful to my labmates, especially

Mr. Ooi Derjun, Mrs. Foong Lianchee, Mrs. Nur Hanisha Azmi, and Mrs. Nadarajan

Sarega for their invaluable help and assistance. As well as, thank to Mr. Zhang Yida on

the collaboration of EBN research.

Finally yet importantly, I would to express my heartiest appreciation and thanks to all

my family members for their understanding and support throughout my studies.

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This thesis was submitted to the Senate of Universiti Putra Malaysia and has been

accepted as fulfillment of the requirement for the degree of Doctor of Philosophy.

The members of the Supervisory Committee were as follows:

Maznah Ismail, PhD

Professor

Institute of Bioscience

Universiti Putra Malaysia

(Chairman)

Aini Ideris, PhD

Professor

Faculty of Veterinary Medicine

Universiti Putra Malaysia

(Member)

Rozi Mahmud, PhD

Professor

Faculty of Medicine and Health Science

Universiti Putra Malaysia

(Member)

BUJANG KIM. HUAT, PhD

Professor and Dean

School of Graduate Studies

Universiti Putra Malaysia

Date:

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Declaration by graduate student

I hereby confirm that:

this thesis is my original work;

quotations, illustrations and citations have been duly referenced;

this thesis has not been submitted previously or concurrently for any other

degree at any other institutions;

intellectual property from the thesis and copyright of thesis are fully -owned by

Universiti Putra Malaysia, as according to the Universiti Putra Malaysia

(Research) Rules 2012;

written permission must be obtained from supervisor and the office of Deputy

Vice-Chancellor (Research and Innovation) before thesis is published (in the

form of written, printed or in electronic form) including books, journals,

modules, proceedings, popular writings, seminar papers, manuscripts, posters,

reports, lecture notes, learning modules or any other materials as stated in the

Universiti Putra Malaysia (Research) Rules 2012 ;

there is no plagiarism or data falsification/fabrication in the thesis, and

scholarly integrity is upheld as according to the Universiti Putra Malaysia

(Graduate Studies) Rules 2003 (Revision 2012-2013) and the Universiti Putra

Malaysia (Research) Rules 2012. The thesis has undergone plagiarism detection

software.

Signature: _______________________ Date: __________________

Name and Matric No.: Hou Zhiping GS34203

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Declaration by members of supervisory committee

This is to confirm that:

the research conducted and the writing of this thesis was under our

supervision;

supervision responsibilities as stated in the Universiti Putra Malaysia (Graduate

Studies) Rules 2003 (Revision 2012-2013) are adhered to.

Signature:

Chairman of Supervisory Committee: Prof. Dr. Maznah Ismail

Signature:

Member of Supervisory Committee: Prof. Dr. Aini Ideris

Signature:

Member of Supervisory Committee: Prof. Dr. Rozi Mahmud

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TABLE OF CONTENTS

Page

ABSTRACT i ABSTRAK iii

ACKNOWLEDGEMENTS v

APPROVAL vi

DECLARATION viii

LIST OF TABLES xiii

LIST OF FIGURES xiv

LIST OF ABBREVIATIONS xvii

CHAPTER

1 INTRODUCTION 1

2 LITERATURE REVIEW 4 2.1.Ageing and ageing - related diseases 4

2.1.1. Physiological and pathological ageing 4 2.1.2. Ageing theory 5 2.1.3. Traditional medicine with anti - ageing and neurodegenerative properties 8 2.1.4. Advantages and disadvantages in different ageing model 8

2.2.Menopause and ageing 12 2.2.2. Effects on brain 14 2.2.3. Cardiovascular effects and diabetes 15 2.2.4. Bone density and osteoporosis 15 2.2.5. Oestrogen therapy in menopausal women 16 2.2.6. Hormone replacement treatment 17

2.3.Edible bird’s nest 18 2.3.1. Authentication and adulteration of EBN 18 2.3.2. Component and properties of EBN 20 2.3.3. Biological functions of EBN 23

3 .EDIBLE BIRD’S NEST INCREASES EXPRESSION OF HIPPOCAMPAL

.SIRTUIN - 1 AND PREVENTS MENOPAUSE-RELATED MEMORY AND

.COGNITIVE DECLINE IN OVARIECTOMIZED RATS 25 3.1 Introduction 25 3.2 Methods and Materials 26

3.2.1. Animal handling and feeding 26 3.2.2. Morris water maze (MWM) behavioural test 28 3.2.3. Preparation of tissue samples 28 3.2.4. Serum urea and creatinine, and liver enzymes 28 3.2.5. Serum oestrogen detection 29 3.2.6. Sirtuin - 1 immunohistochemistry 29 3.2.7. Statistical analysis 29

3.3 Results 29 3.3.1. Food intake, body weight and hormone determination 29 3.3.2. Morris Water Maze 30 3.3.3. Toxicity detection 34 3.3.4. SIRT1 expression in hippocampus 35

3.4. Discussion 37

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3.5. Conclusions 37

4 .EFFECTS OF EDIBLE BIRD’S NEST ON HIPPOCAMPAL AND

CORTICAL NEURODEGENERATION IN OVARIECTOMIZED RATS 38 4.1.Introduction 38 4.2.Materials and methods 39

4.2.1. Materials 39 4.2.2. Animal treatment and operation procedure 39 4.2.3. Observation of estrous cycle 39 4.2.4. Fasting blood glucose and serum insulin levels 40 4.2.5. Serum oestrogen and advanced glycation end-products (AGEs) 40 4.2.6. Superoxide dismutase (SOD) and catalase (CAT) activity assay 40 4.2.7. Thiobarbituric acid reactive substances (TBARS) assay 40 4.2.8. Ribonucleic acid (RNA) extraction, reverse transcription and multiplex

polymerase chain reaction (PCR) analyses 41 4.2.9. Hippocampal and frontal cortical caspase 3 western blotting 41 4.2.10. Statistical analysis 41

4.3.Results 43 4.3.1. Food intake, body weight and biochemical level determination 43 4.3.2. EBN lowered serum AGEs 45 4.3.3. Hippocampal and frontal cortical antioxidant enzyme activities 46 4.3.4. Hippocampal and frontal cortical TBARs 48 4.3.5. mRNA levels of antioxidant and neurodegeneration - related genes 48 4.3.6. EBN attenuated caspase 3 protein level 53

4.4.Discussion 54 4.5.Conclusion 55

5 .NUTRIGENOMICS EFFECTS OF EDIBLE BIRD'S NEST ON INSULIN

.SIGNALLING IN OVARIECTOMISED RATS 57 5.1.Introduction 57 5.2 Materials and Method 58

5.2.1. Materials 58 5.2.2. EBN samples 58 5.2.3. Animal handling and feeding 58 5.2.4. Oral glucose tolerance test and lipid profile 59 5.2.5. Determination of serum oestrogen and insulin 59 5.2.6. Hepatic anti - oxidative markers 59 5.2.7. RNA extraction, reverse transcription and multiplex PCR analyses 60 5.2.8. Statistical analysis 62

5.3 Results and discussion 62 5.3.1. Food intake and body weight 62 5.3.2. Serum lipid profile 64 5.3.3. OGTT, serum insulin and HOMA - IR 65 5.3.4. Hepatic antioxidant capacity of EBN 67 5.3.5. mRNA levels of hepatic insulin signalling genes 68

5.4 Conclusions 74

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6 .LACTOFERRIN AND OVOTRANSFERRIN CONTRIBUTE TOWARD

.ANTIOXIDATIVE EFFECTS OF EDIBLE BIRD’S NEST AGAINST

.HYDROGEN PEROXIDE - INDUCED OXIDATIVE STRESS IN HUMAN .

SH - SY5Y CELLS 75 6.1.Introduction 75 6.2.Materials and Method 76

6.2.1. Materials 76 6.2.2. Preparation of EBN water-soluble protein 76 6.2.3. LF and OVF detection 76 6.2.5. Oxygen radical absorbance capacity (ORAC) assay 77 6.2.6. Cell culture 77 6.2.7. MTT assay 77 6.2.8. Morphological analysis using inverted light microscope 77 6.2.9. Acridine orange and propidium iodide staining 78 6.2.10. SOD and ROS Elisa assays 78 6.2.11. Annexin V - FITC and propidium iodide double - staining assay 78 6.2.12. Measurement of mitochondrial membrane potential (MMP) 78 6.2.13. RNA extraction, reverse transcription and Multiplex PCR analysis 79 6.2.14. Statistical Analysis 80

6.3.Results and Discussion 80 6.3.1. LF and OVF detection in EBN water extraction 80 6.3.2. EBN, LF and OVF attenuate H2O2 - induced cytotoxicity on SH -

SY5Y cells 81 6.3.3. ABTS radical cation scavenging activities and ORAC assay 82 6.3.4. Morphological analysis using inverted light microscope 84 6.3.5. AO / PI staining 85 6.3.6. ROS and SOD assay 85 6.3.7. EBN and the biomarkers attenuated H2O2 - induced apoptosis in SH -

SY5Y cells 87 6.3.8. EBN and its biomarkers prevented H2O2 - induced reduction of MMP

in SH - SY5Y Cells 89 6.3.9. Effects of EBN, LF and OVF on mRNA levels of antioxidant and

apoptosis genes 89 6.4.Conclusions 93

7. GENERAL DISCUSSION 95

8. SUMMARY, GENERAL CONCLUSION AND RECOMMENDATION

FOR FUTURE RESEARCH 98

REFERENCES 99 APPENDICES 119 BIODATA OF STUDENT 127 LIST OF PUBLICATIONS 128

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LIST OF TABLES

Table Page

2.1. Main theory of ageing 12

2.2. Characteristics of animal models used for the research of

human disease 16

2.3. Composition of the edible bird’s nest 40

3.1. Body weights and serum estrogen concentrations of

ovariectomized rats. 59

4.1. Food composition and animal groups 77

4.2. Names, accession number and primer sequences used in the

study 80

4.3. Body weight, tissue weight and length, and serum biochemical

parameters in ovariectomized rats 81

5.1. Nutritional values for Edible Bird’s Nest 102

5.2. Names, accession number and primer sequences used in the

study 106

5.3. Body weights, food intake and serum estrogen in

ovariectomized rats after 12 weeks intervention 108

5.4. Serum lipid profiles after 12 weeks of intervention 110

6.1. Gene name, accession number, reverse and forward primer

sequences used in GeXP multiplex gene expression analyze 133

6.2.A. Lactoferrin and ovotransferrin expression in different types of

Edible Bird’s Nest 135

6.2.B. Lactoferrin and ovotransferrin expression in different species 135

S.1. Morris water maze spatial (hidden platform) start position 192

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LIST OF FIGURES

Figure Page

2.1. The stage of reproductive ageing workshop staging system 23

2.2. A: bone mass changes by ages in male and female; B: description

of standing posture and osteoporosis;

28

3.1. Female Sprague – Dawley rats growing in the in vivo anti – aging

model

53

3.2. Representative path tracings of the Morris Water Maze. 61

3.3. Morris Water Maze (MWM) behavioral test results showing effect

of Edible Bird’s Nest (EBN) on (A) spatial memory acquisition

during MWM; (B) latency to first entry target quardant; (C) time

spent in the target quardant in the probe trial.

62

3.4. Toxicity profiles of Edible Bird’s Nest treatment in ovariectomized

rats in comparison with estrogen. (A) serum alanine transaminase

(ALT); (B) serum alkaline phosphatase (ALP) activities; (C) serum

creatinine (CREA); (D) serum urea activity.

64

3.5. Sirtuin - 1 (SIRT1) immunoreactivity in the Cornus Ammonis

(CA) area 2 of the hippocampus. A) Representative micrographs of

SIRT1 immunoreactivity; B) Histograms showing the optical

density (OD) of SIRT1 immunoreactive neurons.

66

Sirtuin - 1 (SIRT1) immunoreactivity in the Cornus Ammonis

(CA) area 4 of the hippocampus. A) Representative micrographs of

SIRT1 immunoreactivity; B) Histograms showing the optical

density (OD) of SIRT1 immunoreactive neurons.

67

4.1. Serum advanced glycation end-products (AGEs) in ovariectomized

rats after 12 weeks of intervention with edible birds’ nest (EBN) or

estrogen. Ovariectomy group (OVX) had their ovaries surgically

removed while sham control group had the same surgical

procedure as ovariectomized rats but ovaries were left intact.

82

4.2. Hippocampal and frontal cortical tissue A. superoxide dismutase

(SOD), and B. Catalase (CAT) in ovariectomized rats after 12

weeks of intervention with edible birds’ nest (EBN) or estrogen.

84

4.3. Hippocampal and frontal cortical tissue malondialdehyde (MDA)

in ovariectomized rats after 12 weeks of intervention with edible

birds’ nest (EBN) or estrogen.

85

4.4. mRNA levels of superoxide dismutase (SOD) 1, SOD 2, SOD 3

and catalase (CAT) in hippocampal and frontal cortical tissue of

ovariectomized rats after 12 weeks of intervention with edible

birds’ nest (EBN) or estrogen.

88

4.5. mRNA levels of presenilin (PSEN) 1, PSEN 2 and amyloid

precursor protein (APP) in hippocampal and frontal cortical tissue

of ovariectomized rats after 12 weeks of intervention with edible

birds’ nest (EBN) or estrogen.

89

4.6. mRNA levels of insulin degrading enzyme (IDE) and low density

lipoprotein receptor-related protein (LRP) 1 in hippocampal and

frontal cortical tissue of ovariectomized rats after 12 weeks of

intervention with edible birds’ nest (EBN) or estrogen.

90

4.7. Cleaved caspase 3 protein levels shown as A. representative 92

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western blot assay and B. relative optical density in hippocampal

and frontal cortical tissue of ovariectomized rats after 12 weeks of

intervention with edible birds’ nest (EBN) or estrogen.

4.8. Proposed schematic showing how edible birds’ nest (EBN) may

prevent estrogen deficiency-associated neurodegneration.

98

5.1. Effects of 12 weeks supplementation with Edible Bird’s Nest

(EBN) on A. oral glucose tolerance test and B. Area under the

curve for glucose in ovariectomized rats.

112

5.2. Effects of 12 weeks supplementation with Edible Bird’s Nest

(EBN) on A. serum insulin and B. homeostatic model assessment

of insulin resistance (HOMA-IR) in ovariectomized rats.

113

5.3. Effects of 12 weeks supplementation with Edible Bird’s Nest

(EBN) on A. serum superodixe dismutase (SOD) levels and B.

malondyaldehyde (MDA) levels in ovariectomized rats.

115

5.4. Hepatic mRNA levels of A. insulin receptor (Insr), B. insulin

receptor substrate (Irs) 2 and C. Phosphoinositide-3 - kinase

(PI3K) in ovariectomized rats fed with Edible Bird’s Nest (EBN)

for 12 weeks.

119

5.5. Hepatic mRNA levels of A. Glucose transporter (GLUT) 4, B.

Inhibitor of kappa light polypeptide gene enhancer in B-cells,

kinase beta (IKBKB) and C. mitogen-activated protein kinase

(MAPK) 1 in ovariectomized rats fed with Edible Bird’s Nest

(EBN) for 12 weeks.

120

5.6. Hepatic mRNA levels of A. Glucokinase (Gck), B. Potassium

inwardly rectifying channel, subfamily J, member 11 (KCNJ11)

and C. Pyruvate kinase - liver isoform (L - Pk) in ovariectomized

rats fed with Edible Bird’s Nest (EBN) for 12 weeks.

121

5.7. Proposed schematic showing targets of Edible Bird’s Nest (EBN)

action in the insulin signaling pathway.

122

6.1. Effects of edible birds’ nest (EBN), lactoferrin (LF) and

ovotransferrin (OVF) on H2O2 - induced cytotoxicity in SH - SY5Y

cells determined by MTT assay.

137

6.2. ABTS radical cation scavenging activities and oxygen radical

absorbance capacity of edible bird’s nest, lactoferrin (LF) and

ovotransferrin (OVF).

140

6.3. SH-SY5Y cells were captured under inverted light microscope 142

6.4. AO (acridine orange, green) / PI (propidium iodide, red) double

staining on SH - SY5Y human cells under fluorescent microscope.

143

6.5. Superoxide dismutase (SOD) activity (A) and reactive oxygen

species (ROS) generation (B) in SH - SY5Y cells, following

treatment with 1000 μg / ml EBN water extract, 5 µg / ml LF, or

10 µg / ml OVF, and subsequent treatment with or without 250 μM

H2O2, in comparison with untreated control.

145

6.6. (A) Flow cytometry determination of apoptosis on 250 µM H2O2 -

induced SH - SY5Y cells by Annexin V - FITC and PI staining

assay. (B) Effects of EBN, LF and OVF on H2O2 - induced

reduction in Mitochondrial Membrane Potential.

147

6.7. mRNA levels of NF - κB, P53, P38MAPK and Akt genes in SH-

SY5Y cells, following treatment with 1000 μg / ml EBN water

extract, 5 µg / ml LF, 10 µg / mlOVF and subsequent treatment

with 250 μM H2O2, in comparison to untreated control and

152

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treatment with 250 μM H2O2.

6.8. mRNA levels of SOD1, SOD2, and PARP1 genes in SH - SY5Y

cells, following treatment with 1000 μg / ml EBN water extract, 5

µg / ml LF, 10 µg / ml OVF and subsequent treatment with 250

μM H2O2, in comparison to untreated control and treatment with

250 μM H2O2.

153

6.9. Proposed schematic ofEdible Bird’s Nest - induced

neuroprotection activity in the antioxidant and apoptosis pathways.

The neuroprotection of EBN in SH - SY5Y cell line was possibly

related to its ability of anti - oxidant system as well as through

activation of SOD1 / SOD2 / PARP1 transcriptional genes.

155

S.1. The fixed tank for Morris Water Maze. 190

S.2. Computer tracking program monitor Morris Water Maze. 191

S.3. The distribution of Edible Bird’s Nest in Southern East Asia. 196

S.4. A: House Edible Bird Nest (EBN) B: EBN processing procedure,

including raw EBN collection, rinsing and soaking, removing

impurities, modeling and drying

197

S.5. Experimental design of anti – aging properties of Edible Bird’s

Nest in vitro and in vivo studies in animal model

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LIST OF ABBREVIATIONS

AAPH 2,2′ - azobis (2 - amidinopropane) dihydrochloride

ABTS 2,2' - azino - bis (3 - ethylbenzothiazoline - 6 - sulphonic acid)

AGE Advanced glycation end-product

Akt Protein kinase B

ALP Alanine transaminase

ALT Alkaline phosphatase

AO / PI Acridine orange and propidium iodide

APP Amyloid Precursor Protein

ATCC American Type Culture Collection

CA Cornus ammonis

CASP3 Caspase 3

CAT Catalase

CNS Central nervous system

DMEM / F - 12 Minimum essential Eagle’s medium, Ham’s nutrientmixture

DMSO Dimethyl sulfoxide

EBN Edible bird’s nest

EGF Epidermal growth factor

Gapdh Glyceraldehydes - 3 - phosphate dehydrogenase

Gck Gluckokinase

GGT Gamma - glutamyl transferase

GLUT4 Glucose transporter type 4

HDL High density lipoprotein

H2O2 Hydrogen peroxide

HOMA - IR Homeostatic model assessment of insulin resistance

HRT Hormone replacement therapy

IDE Insulin - Degrading Enzyme

Ikbkb Inhibitor of kappa light polypeptide gene enhancer in B - cells,

kinase beta

Insr Insulin receptor

Kan(s) Kanamycin resistance

K2S2O8 Potassium persulphate

KNJC11 Potassium inwardly rectifying channel, subfamily J, member 11

LDL Low density lipoprotein

LF Lactoferrin

LPk Pyruvate kinase-liver isoform

LRP1 Low Density Lipoprotein Receptor - Related Protein1

IRS Insulin receptor substrate

MAPK Mitogen-activated protein kinase

MDA 3,4 - methylenedioxyamphetamine

MMP Mitochondrial membrane potential

MTT 3 - [4,5 - dimethylthiazol - 2 - yl] - 2,5 - diphenyl-tetrazolium

bromide

MWM Morris Water Maze

NaHCO3 Sodium biocarbonate

NF - κB Nuclear factor kappa - light - chain - enhancer of activated B

cells

OD Optical density

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OGTT Oral glucose tolerance test

ORAC Oxygen radical absorbance capacity

OVF Ovotransferrin

OVX Ovariectomy

PARP1 Poly (ADP - ribose) polymerase 1

PI3K Phosphoinositide - 3 - kinase

PSEN1 Presenilin - 1

PSEN2 Presenilin - 2

p53 Cellular tumor antigen p53

MAPK Mitogen-activated protein kinase

RA Retinoic acid

ROS Radical oxygen species

SIRT - 1 Situin - 1

SOD Superoxide dismutase

TBARS Thiobarbituric acid reactive substances

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CHAPTER 1

INTRODUCTION

Biological ageing is the process of cumulative changes to molecular and cellular

structures that disrupt metabolism with the passage of time, resulting in deterioration

and death. Ageing related memory and cognitive decline are increasingly becoming a

problem in humans especially due to improvements in healthcare delivery that have

given rise to increasing longevity. Life expectancy for women is higher than for men

and their menopausal transition is often accompanied with changes. Alteratives in

central nervous system (CNS) are often reflected on memory and cognitive function

and sensitive with body metabolic status. Over the years, the life span of Malaysian

women increased to 76.8 years in 2011 (Malaysia), and the increasing longevity has

meant that women live one -third of their lives beyond cessation of endogenous

oestrogen production from the ovaries (Hara, et al., 2011). Before menopause,

circulating oestrogen level protects women against neurodegenerative diseases, such as

stroke, compared to men (Brann, et al., 2007; Mahesh, & Khan, 2007; Scott,et al., 2012

Vadlamudi, & Brann, 2012). Conversely, postmenopausal women have higher

morbidity and mortality due to neurodegenerative diseases compared with age-matched

men, because of reduced circulating oestrogen level (Appelros, Stegmayr, & Terént,

2009; Persky, Turtzo, & McCullough, 2010). On the other hand, the risk of metabolic

diseases, like type 2 diabetes mellitus, increase significantly in women after

menopause, and they are the burden of neurodegenerative diseases on the basis of

literatures (de la Torre, 2004; Ulas & Cay, 2010).

Oestrogen is secreted and controlled through hypothalamus-pituitary-gonadal (HPG)

axis, to regulate biological function. The decline in oestrogen level in menopause is

reported to result in memory loss and metabolic perturbation soon after it starts, and

sirtuin - 1 protein played important roles in hippocampus dependent memories and

synaptic plasticity as reports. Eventually, low levels of oestrogen lead to other

secondary metabolic abnormalities including oxidative stress, apoptosis and

inflammation that together complicate the ageing-related degenerative diseases through

neuropathy, dementia, Alzheimer’s disease, cardiovascular disease and diabetes. Also,

complications arising from oestrogen - deficit diseases are debilitating and result in a

huge expenditure in health care. In addition, these degenerative diseases that are among

the most common diseases affecting menopausal women, have been linked with

lifestyle especially diet (WHO).

Encouragingly, hormone replacement therapy (HRT) has been shown to prevent

neurodegenerative disorders as conventional usage on treating menopausal symptoms.

However, the risk of life - threatenting complications it induces has limited its use.

Data have reported the effects of long term HRT on the risk of breast cancer (Beral,

Banks, & Reeves, 2002; Tempfer, et al., 2009)and venous thromboembolism (Jick,

Derby, Myers et al., 1996 Vasilakis, & Newton, 1996). Thus, alternatives with better

safety profile compared with conventional HRT have received close attention. Herbal

medicine has a long history of use and is still widely practiced today, based on the

theories, beliefs, and experiences indigenous to different cultures, and used in the

maintenance of health as well as in the prevention, improvement or treatment of

physical and mental illness (Organisation, 2012).

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There is a long history of using traditional medicines in Asian countries. China, one of

the early ancient civilisations, has been using edible bird’s nest (EBN) since ancient

dynasty. EBN is produced by swiftlets from their salivary glue, which is a cementing

substance. The nests are considered to have high nutritional and medicinal values,

traditionally believed to have everything from anti-ageing and anti-cancer properties to

the ability to improve immunity and raise libido. Composition analysis of EBN shows

the major composition is protein (62 % ~ 68 %) including glycoproteins (Hamzah,

Ibrahim, Jaafar et al., 2013), followed by carbohydrate and mineral salts. Additionally,

other bioactives have been reported in EBN including epidermal growth factor (EGF),

testosterone (Marcone, 2005), and chondroitin glycosaminoglycans (Matsukawa,

Matsumoto, Bukawa et al., 2011). Numerous in vitro and in vivo researches have

shown that administration of EBN was able to boost immunity, improve anti-oxidant

ability, promote neutralisation of influenza activity as well as improve osteoporosis .

Sadly, however, evidence-based details of other properties of EBN are lacking. Since

the practical usage of traditional medicine is not strictly enforced under scientific

evidence, herbalism is just recognised as a form of alternative medicine in modern

medicine. Despite EBN’s long history of medicinal use, there is still a dearth of

research and scientific evidence to substantiate the claims of health benefits associated

with anti – ageing including its mechanistic basis.

In this study, it was aimed to explore the evidences for the use of EBN as a functional

food in preventing and managing ageing-related neurodegenerative diseases in

menopause, of which the risk is increased due to loss of protection from oestrogen and

related hormones. The brain cells are normally sensitive to the effect of redox system

because of their peculiar energetic demands (Gandhi & Abramov, 2012). In brain

senescence, radical oxygen species (ROS) starts to accumulate in neurons before

clinically evident signs and symptoms of the disease can be detected (Gandhi &

Abramov, 2012). When ROS accumulate, oxidative damage is normally prevented by

induction of protective factors, like antioxidants. On the other hand, the imbalanced

redox status is involved in advanced glycation end-products (AGEs) adjustment

pathway, and the depletion of cellular antioxidant mechanisms and the generation of

free radicals by AGEs may play a major role in the pathogenesis of neurodegeneration

(Kuhla, 2014; Prasad, et al., 2014). Furthermore, AGEs is influenced by glucose and

lipid homeostasis, and may play the role in transcriptional and proteomic aspects if the

insult is too overwhelming. In such cases, apoptotic mechanisms set in to remove

neurons deemed irreparable (Radi,et al., 2014). Loss of neurons through these apoptotic

deaths results in severe morphological and functional deficits, which manifest with

progressive memory and cognitive decline. Therefore, it was hypothesised that this

research will give clues on the effect of EBN in some selectedof organs and functions

that are affected by low estrogenic level such as memory loss, weight increase, insulin

deficiency and lipid metabolic abnormalities. Their effects on brain and liver related to

anti - oxidation, apoptosis and inflammation were equally considered.

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Hypotheses of the study were:

1. EBN and its bioactives (LF and OVF) protect SH-SY5Y cells against H2O2-

induced cytotoxicity and cell oxidative stress;

2. EBN enhances spatial learning and memory in ovariectomized rats;

3. EBN preserves hippocampal SIRT - 1 activity in the menopause model, as the

likely basis for enhanced spatial learning and memory;

4. EBN is neuroprotective against oestrogen deficiency - induced damage via

increasing serum oestrogen level, and decreasing AGEs and oxidative stress;

5. EBN improves metabolic indices like glucose metabolism, lipid profile and

antioxidant status in ovariectomized rats.

General objective

To study the anti - ageing effects of EBN and its mechanism through in vitro and in

vivo approaches, including transcriptomic and proteomic analyses.

Specific objective

1. To examine the effects of EBN on ovariectomy - induced memory and

cognitive dysfunctions, including transcriptomic and proteomic mechanisms;

as well as to obtain sirtuin-1 data on hippocampus and frontal cortex

parameters;

2. To determine the effects of EBN on serum AGEs and redox status, and neuro -

dysfunction in ovariectomized rats, including mechanistic basis for such

effects;

3. To determine the effects of EBN on weight and metabolic indices related to

insulin resistance in ovariectomized rats, and mechanistic basis for such

effects.

4. To characterize the bioactives (lactoferrin [LF] and ovotransferrin [OVF]) in

EBN, and evaluate their anti - oxidant abilities;

5. To determine the neuroprotective potentials of EBN water extract and its

constituents, LF and OVF, and related molecular mechanisms involved in

H2O2 - induced oxidative stress and apoptosis in SH - SY5Y cells

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